Arterial stiffening is a hallmark of aging and a cholesterol-independent risk factor for cardiovascular disease, but how and why arteries stiffen remain largely unknown. Preliminary studies presented here reveal new insights into the mechanisms of age-dependent arterial stiffening and its link to atherosclerosis. We show that arterial stiffening is accelerated in both apoE-null and LDLR-null mice and that this stiffening is associated with the expression of MMP12 in VSMCs and macrophages. Additionally, we show that the protective effect of gender on arterial stiffness and atherosclerosis in reproductive-age females is associated with an estrogen- mediated inhibition of macrophage MMP12 gene expression. Remarkably, deletion of MMP12 is sufficient to prevent arterial stiffening and eliminate the male gender bias for both arterial stiffening and atherosclerosis. Based on these data, we hypothesize that the links between aging, arterial stiffening, gender, and atherosclerosis can all be broken by blocking the expression or activity of MMP12. Additionally, we extend our recently published work concluding that Cox2 suppresses the expression of ECM genes, including collagen-I, and that this effect opposes arterial stiffening. We propose that Cox2 counteracts the stiffening effect of MMP12, and that the reciprocal effects of Cox2 and MMP12 play central roles in determining overall arterial stiffness. To test these hypotheses, we now propose three aims to: i) define the relationship between MMP12 and arterial stiffening in atherosclerosis, ii) establish the role of age, female gender and estrogen on arterial stiffness, MMP12 expression, and macrophage homing to vessel, and iii) study the functional interactions between Cox2 and MMP12 on arterial stiffening and atherosclerosis.